The urgency and importance of an effective vaccine for HIV is widely appreciated yet many additional viral vaccines are in need of development or improvement; herpesviruses; respiratory; enteric viruses; Hemorrhagic fevers; to name only a few. Remarkable advances in molecular biology and cellular immunology have set the stage for a new era of vaccine development. The goals of this program project are these: 1) To examine the induction, evolution, and stability of virus-specific T lymphocyte responses to a persistent virus infection (Epstein-Barr Virus) and to a non-persistent virus infection without repeated antigenic exposure (vaccinia); 2) To study the effects of unrelated antigens on the evolution of virus-specific memory T lymphocyte populations; 3) To examine the goals outlined in 1 and 2 across the age spectrum; The Program Project format affords the promise of generating a comprehensive understanding of virus-specific memory T lymphocyte responses in humans than could be achieved by investigators working in isolation. Project #1 will extend our quantitative and qualitative analyses of the EBV epitope-specific CTL response and test the hypothesis that the nature of this response will be different in adults, who often develop severe symptoms, and children, who are often asymptomatic. Project #2 will test the hypothesis that crossreactive T cell responses between different viruses are common during viral infections and that memory T cells specific to previously encountered viruses may become activated by a heterologous virus infection. Project #3 will use vaccinia virus infection as a system to examine T cell responses to a non-persistent virus only encountered once in a lifetime. Three Core Facilities will facilitate the work of these projects. The Administrative and Clinical Core will provide scientific/fiscal oversight and provide clinical samples. The Tetramer Core will provide HLA Class I/peptide tetramers for CD8 T lymphocyte assays. The Cell Science Core will provide reagents, cell separation, establishment and maintenance of cell lines. This Program will result in a deeper understanding of virus-specific T cell responses in humans, which will facilitate the development of new and improved vaccines for use in humans.